Retinal neovascularization is a condition in which new blood vessels grow and proliferate in the retina, typically in response to a decrease in blood flow to the retina. Neovascularization typically improves the flow of blood in a tissue by creating new blood vessels instead of replacing the existing vasculature. The retina possesses a complex architecture of capillaries that supports many different neuronal and photoreceptor cells without interfering with the images that pass through the lens and are processed on the retina's surface. The formation of new blood vessels may destroy this complex architecture and detract from normal functioning of the eye by presenting abnormal conditions such as bleeding, which may cause hazy vision or even total vision loss, and scarring, which may result in retinal dislocation or invasion of the retina from underlying tissue. Neovascularization may progress slowly, resulting generally in the formation of new vessels and fibrous tissue, or rapidly, in which case widespread capillary closure, soft exudate formation, hemorrhages, and blindness are typical.
Neovascular diseases of the retina include diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, retinopathy of prematurity, sickle-cell retinopathy, retinal vein occlusion, oxygen induced retinopathy, and neovascularization due to ocular insults such as traumatic or surgical injury, or transplantation of eye tissue. Other conditions or diseases associated with the manifestation of retinal neovasularization include any disease or condition where a part of the retina is subject to a relatively non-perfused state compared to surrounding tissue, where any one or more of the proteins, proteinases, hormones, or cellular signals associated with angiogenesis are detected, or where new vessel growth can be detected or observed. In addition, diseases implicating matrix metalloproteinase activity, endothelial invasion, or the generation of new blood vessels may also be associated with retinal neovascularization according to this invention.
Neovascularization involves both the degradation of tissue through enzymatic action and the formation of new tissue. A crucial event in the retinal neovascularization process is the migration of epithelial cells, which involves proteolysis of basement membrane components, typically by one or more proteinases. At active neovascularization sites, both the high (54 kD) and low (33 kD) molecular weight forms of the protein urokinase have been found at levels significantly higher than in normal retinas. The levels of both pro and active forms of the matrix metalloproteinases (MMP) MMP-2 (gelatinase) and MMP-9 are also significantly elevated in neovascular membranes in comparison to normal retinas. (See Das et al., Investigative Ophthalmology & Visual Sciences 40:809–13 (1999); Coors et al., Investigative Ophthalmology & Visual Sciences 40(4):S231 (1999)). Typically the active forms of MMPs such as collagenase, stromelysin and gelatinase are not present at detectable levels in normal retinas.
Diabetic retinopathy is the leading cause of blindness among working age adults in the United States. Initially, the high blood glucose levels common to persons with diabetes mellitus cause an increase in growth factor levels in the eyes. This condition is known as the “pre-diabetic retinopathy stage” and can lead to retinopathy if not prophylactically treated. Non-proliferative or early-stage diabetic retinopathy, also known as “background diabetic retinopathy,” is characterized by thickening of the basement membrane, loss of retinal pericytes, microvascular abnormalities, intraretinal microaneurysms, retinal hemorrhages (known as “dot blot” or “cotton wool” spots), retinal edema, capillary closure, and soft and hard exudates. Late-stage or proliferative diabetic retinopathy, which is characterized by neovascularization and fibrovascular growth, i.e., scarring involving glial and fibrous elements, from the retina or optic nerve over the inner surface of the retina or into the vitreous cavity. Retinal detachment may also occur.
Age-related macular degeneration is one of the leading causes of blindness in older adults in the United States, and may account for up to 30 percent of all bilateral blindness among Caucasian Americans. This disease is characterized by loss of central vision, usually in both eyes, due to damage to the retinal pigment epithelial (RPE) cells. RPE cells are aligned in the lowest layer of the retina, on the Bruch's membrane, and absorb the light which reaches the retina so as to prevent reflection. RPE cells also constitute the blood-retinal barrier which partitions the visual cells and the vascular layer of choroid together with the Bruch's membrane. In general, RPE cells have important physical and physiological functions, such as sustainment and regeneration of visual cells.
Retinopathy of prematurity (ROP) is a common cause of blindness in children in the United States. Premature infants are exposed to hyperoxic conditions after birth even without the administration of supplemental oxygen due to the higher partial pressure of oxygen in the atmosphere as compared to in utero conditions. This relative hyperoxia is necessary for the survival of premature infants yet may result in ROP. The hyperoxic atmosphere causes retinal blood vessels to stop developing into the peripheral retina, resulting in ischemia and localized hypoxic conditions as the metabolic demands of the developing retina increase. The resulting localized hypoxia stimulates retinal neovascularization. The neovascularization usually regresses, but may lead to irreversible vision loss. There are at least 10,000 new cases per year of ROP with a worldwide estimate of 10 million total cases.
Known treatments for retinal neovascularization include panretinal laser coagulation, cryotherapy, laser therapy, and chemotherapy. Panretinal laser coagulation is the classic treatment for proliferative diabetic retinopathy, but may have serious side effects such as foveal burns, hemorrhaging, retinal detachment, choroidal vessel growth, decreased peripheral and night vision, and changes in color perception. Cryotherapy and laser therapy may be used to treat ROP and other neovascular diseases, but are not completely effective and may damage the eye and result in decreased vision. In some diseases such as exudative cases of age-related macular degeneration, temporary prevention of vision loss may be achieved by laser therapy, but no permanent treatment is available for some forms of diseases associated with retinal neovascularization.
Chemotherapy has advantages compared to photocoagulation and cryotherapy in that the tissue invasion is smaller and the stress placed on the ocular tissue is lower. The number of effective drugs, however, is quite small. Compounds which inhibit the action of MMPs involved in connective tissue breakdown are of potential value in the treatment of angiogenesis-dependent diseases such as proliferative retinopathies, neovascular glaucoma, and other forms of retinal neovascularization. Certain agents have been proposed for inhibiting MMPs (see U.S. Pat. No. 5,917,090). In particular, MMP inhibitors have been employed as potential treatments to the retina via intraorbital administration, tissue specific microinjection, or intravitreal injection (see, e.g., European Patent Publication EP 0930067, published Jul. 21, 1999; U.S. Pat. No. 5,260,059; and published PCT Application WO 97/18835). While these treatments may act directly at the retina, they have the disadvantage of being difficult to administer and of requiring the co-administration of anesthetic to the patient.
Topical treatment would be preferred because a topical composition may be self-administered by a patient, and does not require the co-administration of anesthetics. Topical compositions are generally ineffective at delivering a therapeutically effective amount of an active ingredient to the retina, however, due to a lack of permeation through the conjunctiva and sclera, and the presence of the blood-retinal barrier. Some ophthalmic treatment agents, such as the highly soluble β-blocking agents, have been found to reach the retina after topical administration because they are absorbed into the blood stream and passed systemically to the retina (see Osborne et al., Exp. Eye Res. 69:331–42). This method is ineffective for relatively insoluble agents, such as MMP inhibitors, that do not pass through the blood-retinal barrier.
What is needed is a topical ophthalmic composition for the prophylactic and therapeutic treatment of retinal neovascularization that is capable of delivering a therapeutically effective amount of an active ingredient to the retina. Also needed are methods for prophylactic and therapeutic treatments of retinal neovascularization.